|[May 10, 2014]
Gilead Announces Results from Phase 2 Study Showing Reduction in Atrial Fibrillation Burden with the Investigational Combination of Ranolazine and Low-Dose Dronedarone
SAN FRANCISCO --(Business Wire)--
Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from
HARMONY, a randomized, double-blind, placebo-controlled Phase 2 study
evaluating the effect of ranolazine and low-dose dronedarone, each given
alone and in combination, on atrial fibrillation burden (AFB) in
patients with paroxysmal atrial fibrillation (AF). In HARMONY, the
combination of ranolazine and low-dose dronedarone provided greater
reductions in AFB from baseline than either therapy used alone. Detailed
results from the study (Abstract #LB03-05) will be presented today
during a late-breaking clinical trials session at the annual meeting of
the Heart Rhythm Society in San Francisco.
Ranolazine is approved in the United States under the tradename Ranexa®
for the treatment of chronic angina at marketed doses of 500 mg and
1,000 mg twice daily. Ranexa with or without dronedarone is not approved
for the treatment of AF.
In the study, patients in the ranolazine 750 mg / dronedarone 150 mg
(RD150) and ranolazine 750 mg / dronedarone 225 mg (RD225) arms
experienced respective reductions of 45 percent and 59 percent in AFB
from baseline over 12 weeks (p=0.072 and p=0.008, respectively, versus
placebo). Among patients receiving RD225, 45 percent achieved AFB
reductions from baseline of =70 percent over 12 weeks. Neither
ranolazine 750 mg (p=0.49) nor dronedarone 225 mg (p=0.78) alone caused
statistically significant reductions in AFB from baseline compared to
placebo. These results are consistent with pre-clinical findings of a
synergistic effect when these therapies are used in combination.
"There currently are a limited number of safe and effective
anti-arrhythmic therapies for AF patients, underscoring the need to
evaluate new treatment strategies," said Peter R. Kowey, MD, William
Wikoff Smith Chair in Cardiovascular Research, Lankenau Medical Center
and Professor of Medicine and Clinical Pharmacology, Jefferson Medical
College, Thomas Jefferson University. "HARMONY suggests that a new
therapeutic approach of combining ranolazine and low-dose dronedarone is
more effective than either therapy alone in lowering AF burden. Pending
larger Phase 3 evaluation, a combination of ranolazine and low-dose
dronedarone has the potential to help address a significant and growing
unmet need for additional treatment options for people living with this
In HARMONY, 134 patients were randomized to one of five treatment arms:
placebo (n=26); ranolazine 750 mg tablet twice daily (n=26); dronedarone
225 mg capsule twice daily (n=26); RD150 twice daily (n=26); or RD225
twice daily (n=27).
There was no clinically significant difference between active treatment
groups in the overall incidence of adverse events or adverse events
leading to discontinuations. Among the most frequent adverse events
leading to discontinuation within each treatment group were: atrial
fibrillation (placebo, two patients), vertigo and dizziness (ranolazine
750 mg, two patients each), dyspnea and pruritus (dronedarone 225 mg,
two patients each), hypotension (RD225, two patients) and no adverse
events leading to discontinuation were reported for more than one
patient in the RD150 group (e.g., dizziness and constipation).
The primary endpoint was change in AFB over 12 weeks. AFB was defined as
the total time a patient was in atrial tachycardia/atrial fibrillation
expressed as percentage of total recording time continuously from 0 to
About Atrial Fibrillation (AF)
AF is the most common type of abnormal heartbeat, or arrhythmia. It is
caused by abnormal electrical discharges in the atria (upper two
chambers of the heart), which prevent the heart from pumping blood
normally, and usually causing the heart to beat too rapidly. Symptoms
include palpitations, dizziness, fatigue and shortness of breath, with
complications that can include heart failure and stroke. Currnt
treatment options are aimed at controlling underlying causes,
maintaining sinus rhythm (anti-arrhythmic therapies), slowing the heart
rate and stroke prevention using blood-thinning medications.
About Gilead's Ranolazine/Dronedarone FDC
Ranolazine is approved under the tradename Ranexa® as a
treatment for chronic angina at doses of 500 mg and 1000 mg. Dronedarone
is approved for treatment in patients with a history of paroxysmal or
persistent AF at 400 mg twice daily.
Preclinical data published in the Journal of the American College of
Cardiology in 2010 suggested the combination of ranolazine and
dronedarone has synergistic effects, with greater suppression of atrial
fibrillation (AF) than either of the two therapies alone. Based on this
research and on results from the Phase 2 HARMONY study, Gilead is
currently planning Phase 3 clinical trials for a fixed-dose combination
(FDC) of ranolazine and low-dose dronedarone for paroxysmal/persistent
The Ranolazine/Dronedarone FDC is an investigational product and its
safety and efficacy have not been established. Ranexa is not approved
for treatment of paroxysmal or persistent AF.
Important Safety Information about Ranexa
(Ranolazine) in Chronic Angina
Ranexa is indicated for the treatment of chronic angina.
Ranexa may be used with beta-blockers, nitrates, calcium channel
blockers, anti-platelet therapy, lipid-lowering therapy, ACE
inhibitors, and angiotensin receptor blockers.
Ranexa is contraindicated in patients:
Taking strong inhibitors of CYP3A (e.g., ketoconazole,
itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir,
indinavir, and saquinavir).
Taking inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine,
phenobarbital, phenytoin, carbamazepine, and St John's wort)
With liver cirrhosis
Warnings and Precautions
Ranexa blocks lKr and prolongs the QTc interval in a
Clinical experience in an acute coronary syndrome population did not
show an increased risk of proarrhythmia or sudden death. However,
there is little experience with high doses (> 1000 mg twice daily) or
exposure, with other QT-prolonging drugs, with potassium channel
variants resulting in a long QT interval, in patients with a family
history of (or congenital) long QT syndrome, or in patients with known
acquired QT interval prolongation.
Acute renal failure has been observed in patients with severe renal
impairment while on Ranexa. Monitor renal function after initiation
and periodically in patients with moderate to severe renal impairment.
Discontinue Ranexa if acute renal failure develops.
The most common adverse reactions (> 4 percent and more common than
with placebo) during treatment with Ranexa were dizziness, headache,
constipation, and nausea.
Dosage and Administration
Begin treatment with 500 mg twice daily and increase to the maximum
recommended dose of 1000 mg twice daily, based on clinical symptoms.
Ranexa should be swallowed whole; do not crush, break or chew.
Limit the dose of Ranexa to 500 mg twice daily in patients on moderate
CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin,
fluconazole, and grapefruit juice or grapefruit-containing products). See
Drug Interactions for additional dosing considerations.
Inducers and strong inhibitors of CYP3A: Do not use Ranexa (see
Moderate CYP3A inhibitors: Limit Ranexa to 500 mg twice daily
(see Dosage and Administration).
P-gp inhibitors (e.g., cyclosporine): Ranexa exposure
increased; titrate Ranexa based on clinical response.
CYP3A substrates: Limit simvastatin to 20 mg once daily when
used with Ranexa. Doses of other sensitive CYP3A substrates (e.g.,
lovastatin) and CYP3A substrates with narrow therapeutic range (e.g.,
cyclosporine, tacrolimus, sirolimus) may need to be reduced with
Drugs transported by P-gp (e.g., digoxin) or metabolized by CYP2D6
(e.g., tricyclic antidepressants and antipsychotics): Doses of
these drugs may need to be reduced.
Drugs transported by OCT2: Limit metformin to 1700 mg
per day when used with Ranexa 1000 mg twice daily. Monitor blood
glucose and risks associated with high metformin exposure.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops
and commercializes innovative therapeutics in areas of unmet medical
need. The company's mission is to advance the care of patients suffering
from life-threatening diseases worldwide. Headquartered in Foster City,
California, Gilead has operations in North and South
America, Europe and Asia Pacific.
This press release includes forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995 that are
subject to risks, uncertainties and other factors, including the
possibility of unfavorable results from additional clinical trials
involving an FDC of ranolazine and low-dose dronedarone. In addition,
Gilead may be unable to initiate the Phase 3 trials for an FDC of
ranolazine and low-dose dronedarone for paroxysmal/persistent
(non-permanent) AF in the currently anticipated timelines and may be
unable to enroll patients in the studies and may need to modify or delay
these studies. Further, Gilead may make a strategic decision to
discontinue development of an FDC of ranolazine and low-dose dronedarone
if, for example, Gilead believes commercialization will be difficult
relative to other opportunities in its pipeline. As a result, an FDC of
ranolazine and low-dose dronedarone may never be commercialized. These
risks, uncertainties and other factors could cause actual results to
differ materially from those referred to in the forward-looking
statements. The reader is cautioned not to rely on these forward-looking
statements. These and other risks are described in detail in Gilead's
Quarterly Report on Form 10-Q for the quarter ended March 31, 2014, as
filed with the U.S. Securities and Exchange Commission. All
forward-looking statements are based on information currently available
to Gilead, and Gilead assumes no obligation to update any such
U.S. full prescribing information for Ranexa®
is available at www.gilead.com.
Ranexa is a registered trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the company's
website at www.gilead.com,
follow Gilead on Twitter (News - Alert) (@GileadSciences) or call Gilead Public Affairs
at 1-800-GILEAD-5 or 1-650-574-3000.
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